Widespread and tissue specific age-related DNA methylation changes in mice.

Aberrant methylation of promoter CpG islands in cancer is associated with silencing of tumor-suppressor genes, and age-dependent hypermethylation in normal appearing mucosa may be a risk factor for human colon cancer. It is not known whether this age-related DNA methylation phenomenon is specific to human tissues. We performed comprehensive DNA methylation profiling of promoter regions in aging mouse intestine using methylated CpG island amplification in combination with microarray analysis. By comparing C57BL/6 mice at 3-mo-old versus 35-mo-old for 3627 detectable autosomal genes, we found 774 (21%) that showed increased methylation and 466 (13%) that showed decreased methylation. We used pyrosequencing to quantitatively validate the microarray data and confirmed linear age-related methylation changes for all 12 genomic regions examined. We then examined 11 changed genomic loci for age-related methylation in other tissues. Of these, three of 11 showed similar changes in lung, seven of 11 changed in liver, and six of 11 changed in spleen, though to a lower degree than the changes seen in colon. There was partial conservation between age-related hypermethylation in human and mouse intestines, and Polycomb targets in embryonic stem cells were enriched among the hypermethylated genes. Our findings demonstrate a surprisingly high rate of hyper- and hypomethylation as a function of age in normal mouse small intestine tissues and a strong tissue-specificity to the process. We conclude that epigenetic deregulation is a common feature of aging in mammals.

[1]  Paul Marjoram,et al.  Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers , 2009, Proceedings of the National Academy of Sciences.

[2]  A. Riggs,et al.  Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. , 2008, Cancer research.

[3]  B. Lyn‐Cook,et al.  Age and gender affect DNMT3a and DNMT3b expression in human liver , 2008, Cell Biology and Toxicology.

[4]  J. Issa.  DNA methylation as a therapeutic target in cancer. , 2008, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  Yan-shen Peng,et al.  The Expression and Clinical Significance of DNA Methyltransferase Proteins in Human Gastric Cancer , 2008, Digestive Diseases and Sciences.

[6]  R. Jaenisch,et al.  Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. , 2007, Genes & development.

[7]  Yi Guo,et al.  Genome-Wide Profiling of DNA Methylation Reveals a Class of Normally Methylated CpG Island Promoters , 2007, PLoS genetics.

[8]  J. Issa,et al.  LINE-1 Hypomethylation in Cancer Is Highly Variable and Inversely Correlated with Microsatellite Instability , 2007, PloS one.

[9]  A. Riggs,et al.  Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay , 2007, Proceedings of the National Academy of Sciences.

[10]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[11]  P. Laird,et al.  Epigenetic stem cell signature in cancer , 2007, Nature Genetics.

[12]  Zohar Yakhini,et al.  Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer , 2007, Nature Genetics.

[13]  Kelly M. McGarvey,et al.  A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing , 2007, Nature Genetics.

[14]  J. Rogers,et al.  DNA methylation profiling of human chromosomes 6, 20 and 22 , 2006, Nature Genetics.

[15]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[16]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[17]  J. Liepnieks,et al.  Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[18]  M. Toyota,et al.  Epigenetic changes in solid and hematopoietic tumors. , 2005, Seminars in oncology.

[19]  P. Laird,et al.  Gene-Specific Methylation and Subsequent Risk of Colorectal Adenomas among Participants of the Polyp Prevention Trial , 2005, Cancer Epidemiology Biomarkers & Prevention.

[20]  Jian Yu,et al.  Methylation profile of the promoter CpG islands of 31 genes that may contribute to colorectal carcinogenesis. , 2004, World Journal of Gastroenterology.

[21]  J. Issa.  CpG island methylator phenotype in cancer , 2004, Nature Reviews Cancer.

[22]  Bing Zhang,et al.  GOTree Machine (GOTM): a web-based platform for interpreting sets of interesting genes using Gene Ontology hierarchies , 2004, BMC Bioinformatics.

[23]  Kazuhiro Yoshida,et al.  Promoter methylation of cyclin D2 gene in gastric carcinoma. , 2003, International journal of oncology.

[24]  J. Herman,et al.  Gene silencing in cancer in association with promoter hypermethylation. , 2003, The New England journal of medicine.

[25]  Hyeon Joo Lee,et al.  Aberrant CpG island hypermethylation of chronic gastritis, in relation to aging, gender, intestinal metaplasia, and chronic inflammation. , 2003, The American journal of pathology.

[26]  Eva K. Lee,et al.  Predicting aberrant CpG island methylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Stan Pounds,et al.  Estimating the Occurrence of False Positives and False Negatives in Microarray Studies by Approximating and Partitioning the Empirical Distribution of P-values , 2003, Bioinform..

[28]  T. Motoyama,et al.  Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples , 2003, Oncogene.

[29]  R. Kuick,et al.  Infrequent occurrence of age-dependent changes in CpG island methylation as detected by restriction landmark genome scanning , 2002, Mechanisms of Ageing and Development.

[30]  M. Ehrlich,et al.  DNA methylation in cancer: too much, but also too little , 2002, Oncogene.

[31]  Kyoung-Mee Kim,et al.  Methylation reveals a niche: stem cell succession in human colon crypts , 2002, Oncogene.

[32]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[33]  Nita Ahuja,et al.  DNA methylation and environmental exposures in human hepatocellular carcinoma. , 2002, Journal of the National Cancer Institute.

[34]  M. Toyota,et al.  Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors , 2002, Oncogene.

[35]  S. Tavaré,et al.  Investigating stem cells in human colon by using methylation patterns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  N. Ahuja,et al.  Accelerated age-related CpG island methylation in ulcerative colitis. , 2001, Cancer research.

[37]  S. Nishizuka,et al.  Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia , 2000, Oncogene.

[38]  N. Ahuja,et al.  Aging, methylation and cancer. , 2000, Histology and histopathology.

[39]  P. Laird,et al.  CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. , 1999, Cancer research.

[40]  S. Baylin,et al.  Aging and DNA methylation in colorectal mucosa and cancer. , 1998, Cancer research.

[41]  S. Cross,et al.  CpG islands and genes. , 1995, Current opinion in genetics & development.

[42]  R. Weinberg,et al.  Suppression of intestinal neoplasia by DNA hypomethylation , 1995, Cell.

[43]  A. Bird,et al.  Number of CpG islands and genes in human and mouse. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Oliver Clay,et al.  Evidence for erosion of mouse CpG islands during mammalian evolution , 1993, Somatic cell and molecular genetics.

[45]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[46]  W. Cleveland.  Robust Locally Weighted Regression and Smoothing Scatterplots , 1979 .

[47]  S. Kakar,et al.  CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component. , 2008, Human pathology.

[48]  J. Issa,et al.  Epigenetic changes in colorectal cancer , 2004, Cancer and Metastasis Reviews.

[49]  J. Cameron,et al.  Overexpression of S100A4 in pancreatic ductal adenocarcinomas is associated with poor differentiation and DNA hypomethylation. , 2002, The American journal of pathology.

[50]  P. Laird,et al.  Adenocarcinoma Epigenetic Patterns in the Progression of Esophageal Updated Version , 2001 .

[51]  J. Issa.  The epigenetics of colorectal cancer. , 2000, Annals of the New York Academy of Sciences.

[52]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[53]  S. Baylin,et al.  Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon , 1994, Nature Genetics.